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Czachorowski M.J.,Genetic and Molecular Epidemiology Group | Amaral A.F.S.,Genetic and Molecular Epidemiology Group | Montes-Moreno S.,Hospital Universitario Marques Of Valdecilla | Lloreta J.,Institute Municipal dInvestigacio Medica Hospital del Mar | And 9 more authors.
PLoS ONE | Year: 2012

Aberrant overexpression of cyclooxygenase-2 (COX2) is observed in urothelial carcinoma of the bladder (UCB). Studies evaluating COX2 as a prognostic marker in UCB report contradictory results. We determined the prognostic potential of COX2 expression in UCB and quantitatively summarize the results with those of the literature through a meta-analysis. Newly diagnosed UCB patients recruited between 1998-2001 in 18 Spanish hospitals were prospectively included in the study and followed-up (median, 70.7 months). Diagnostic slides were reviewed and uniformly classified by expert pathologists. Clinical data was retrieved from hospital charts. Tissue microarrays containing non-muscle invasive (n = 557) and muscle invasive (n = 216) tumours were analyzed by immunohistochemistry using quantitative image analysis. Expression was evaluated in Cox regression models to assess the risk of recurrence, progression and disease-specific mortality. Meta-hazard ratios were estimated using our results and those from 11 additional evaluable studies. COX2 expression was observed in 38% (211/557) of non-muscle invasive and 63% (137/216) of muscle invasive tumors. Expression was associated with advanced pathological stage and grade (p<0.0001). In the univariable analyses, COX2 expression - as a categorical variable - was not associated with any of the outcomes analyzed. As a continuous variable, a weak association with recurrence in non-muscle invasive tumors was observed (p-value = 0.048). In the multivariable analyses, COX2 expression did not independently predict any of the considered outcomes. The meta-analysis confirmed these results. We did not find evidence that COX2 expression is an independent prognostic marker of recurrence, progression or survival in patients with UCB. © 2012 Czachorowski et al.

Molero X.,Autonomous University of Barcelona | Vaquero E.C.,Autonomous University of Barcelona | Flandez M.,CSIC - National Center for Metallurgical Research | Gonzalez A.M.,Autonomous University of Barcelona | And 12 more authors.
Gut | Year: 2012

Objectives: During pancreatitis, specific transcriptional programmes govern functional regeneration after injury. The objective of this study was to analyse the dynamic regulation of pancreatic genes and the role of transcriptional regulators during recovery from pancreatitis. Design: Wild-type and genetically modified mice (Hnf1α -/- and Ptf1a +/-) were used. After caerulein or L-arginine induced pancreatitis, blood or pancreata were processed for enzymatic assays, ELISA, histology, immunohistochemistry, western blotting and quantitative reverse transcriptase-PCR. Nr5a2 promoter reporter and chromatin immunoprecipitation assays for Hnf1α were also performed. Results: After caerulein pancreatic injury, expression of acinar and endocrine genes rapidly decreased, but eventually recovered, depicting distinct cell-type-specific patterns. Pdx1 and Hnf1α mRNAs underwent marked downregulation, matching endocrine/exocrine gene expression profiles. Ptf1a, Pdx1 and Hnf1α protein levels were also reduced and recovered gradually. These changes were associated with transient impairment of exocrine and endocrine function, including abnormal glucose tolerance. On L-arginine pancreatitis, changes in Ptf1a, Pdx1 and Hnf1α gene and protein expression were recapitulated. Reduced Hnf1α and Ptf1a levels after pancreatitis coincided with increased acinar cell proliferation, both in Hnf1α -/- and Ptf1a +/- mice. Moreover, Hnf1α -/- mice had reduced Ptf1a protein as well as transcripts for Ptf1a and digestive enzymes. Dispersed acini from Hnf1α -/-mice showed suboptimal secretory responses to caerulein. Bioinformatics analysis did not support a role for Hnf1α as a direct regulator of digestive enzyme genes. Instead, it was found that Hnf1α binds to, and regulates, the promoter of Nr5a2, coding an orphan nuclear receptor that regulates acinar gene expression. Conclusions: Dynamic changes in gene expression occur on pancreatitis induction, determining altered exocrine and endocrine function. This analysis uncovers roles for Hnf1αin the regulation of acinar cell determination and function. This effect may be mediated, in part, through direct regulation of Nr5a2.

De La Torre-Carbot K.,University of Barcelona | De La Torre-Carbot K.,CIBER ISCIII | Chavez-Servin J.L.,University of Barcelona | Chavez-Servin J.L.,CIBER ISCIII | And 14 more authors.
Journal of Nutrition | Year: 2010

In human LDL, the bioactivity of olive oil phenols is determined by the in vivo disposition of the biological metabolites of these compounds. Here, we examined how the ingestion of 2 similar olive oils affected the content of the metabolic forms of olive oil phenols in LDL in men. The oils differed in phenol concentrations as follows: high (629 mg/L) for virgin olive oil (VOO) and null (0 mg/L) for refined olive oil (ROO). The study population consisted of a subsample from the EUROLIVE study and a randomized controlled, crossover design was used. Intervention periods lasted 3 wk and were preceded by a 2-wk washout period. The levels of LDL hydroxytyrosol monosulfate and homovanillic acid sulfate, but not of tyrosol sulfate, increased after VOO ingestion (P < 0.05), whereas the concentrations of circulating oxidation markers, including oxidized LDL (oxLDL), conjugated dienes, and hydroxy fatty acids, decreased (P < 0.05). The levels of LDL phenols and oxidation markers were not affected by ROO consumption. The relative increase in the 3 LDL phenols was greater when men consumed VOO than when they consumed ROO (P < 0.05), as was the relative decrease in plasma oxLDL (P = 0.001) and hydroxy fatty acids (P < 0.001). Plasma oxLDL concentrations were negatively correlated with the LDL phenol levels (r = -0.296; P = 0.013). Phenols in LDL were not associated with other oxidation markers. In summary, the phenol concentration of olive oil modulates the phenolic metabolite content in LDL after sustained, daily consumption. The inverse relationship of these metabolites with the degree of LDL oxidation supports the in vivo antioxidant role of olive oil phenolics compounds. © 2010 American Society for Nutrition.

Guey L.T.,Spanish National Cancer Research Center | Guey L.T.,Institute Municipal dInvestigacio Medica Hospital del Mar | Garcia-Closas M.,U.S. National Cancer Institute | Murta-Nascimento C.,Institute Municipal dInvestigacio Medica Hospital del Mar | And 22 more authors.
European Urology | Year: 2010

Background: Clinical, pathologic, and molecular evidence indicate that bladder cancer is heterogeneous with pathologic/molecular features that define distinct subphenotypes with different prognoses. It is conceivable that specific patterns of genetic susceptibility are associated with particular subphenotypes. Objective: To examine evidence for the contribution of germline genetic variation to bladder cancer heterogeneity. Design, setting, and participants: The Spanish Bladder Cancer/EPICURO Study is a case-control study based in 18 hospitals located in five areas in Spain. Cases were patients with a newly diagnosed, histologically confirmed, urothelial cell carcinoma of the bladder from 1998 to 2001. Case diagnoses were reviewed and uniformly classified by pathologists following the World Health Organisation/International Society of Urological Pathology 1999 criteria. Controls were hospital-matched patients (n = 1149). Measurements: A total of 1526 candidate variants in 423 candidate genes were analysed. Three distinct subphenotypes were defined according to stage and grade: low-grade nonmuscle invasive (n = 586), high-grade nonmuscle invasive (n = 219), and muscle invasive (n = 246). The association between each variant and subphenotype was assessed by polytomous risk models adjusting for potential confounders. Heterogeneity in genetic susceptibility among subphenotypes was also tested. Results and limitations: Two established bladder cancer susceptibility genotypes, NAT2 slow-acetylation and GSTM1-null, exhibited similar associations among the subphenotypes, as did VEGF-rs25648, which was previously identified in our study. Other variants conferred risks for specific tumour subphenotypes such as PMS2-rs6463524 and CD4-rs3213427 (respective heterogeneity p values of 0.006 and 0.004), which were associated with muscle-invasive tumours (per-allele odds ratios [95% confidence interval] of 0.56 [0.41-0.77] and 0.71 [0.57-0.88], respectively) but not with non-muscle-invasive tumours. Heterogeneity p values were not robust in multiple testing according to their false-discovery rate. Conclusions: These exploratory analyses suggest that genetic susceptibility loci might be related to the molecular/pathologic diversity of bladder cancer. Validation through large-scale replication studies and the study of additional genes and single nucleotide polymorphisms are required. © 2009 European Association of Urology.

PubMed | Conselleria de Sanitat, Center for Research in Environmental Epidemiology, University of the Basque Country, University Pompeu Fabra and 4 more.
Type: Journal Article | Journal: American journal of obstetrics and gynecology | Year: 2015

We sought to assess the association between prenatal head growth and child neuropsychological development in the general population.We evaluated 2104 children at the age of 14 months from a population-based birth cohort in Spain. Head circumference (HC) was measured by ultrasound examinations at weeks 12, 20, and 34 of gestation and by a nurse at birth. Head growth was assessed using conditional SD scores between weeks 12-20 and 20-34. Trained psychologists assessed neuropsychological functioning using the Bayley Scales of Infant Development. Head size measurements at birth were transformed into a 3-category variable: microcephalic (<10th percentile), normocephalic (10th and <90th percentile), and macrocephalic (90th percentile) based on the cohort distribution. P values<.05 were considered statistically significant.No overall associations were observed between HC or head growth and mental and psychomotor scores. In particular, no associations were found between HC at birth and mental scores (coefficient, 0.04; 95% confidence interval, -0.02 to 0.09) and between interval head growth (20-34 weeks) and mental scores (0.31; 95% confidence interval, -0.36 to 0.99). Upon stratification by microcephalic, normocephalic, or macrocephalic head size, results were imprecise, although there were some significant associations in the microcephalic and macrocephalic groups. Adjustment by various child and maternal cofactors did not affect results. The minimum sample size required for present study was 883 patients (=2, =0.05, power=0.80).Overall prenatal and perinatal HC was not associated with 14-month-old neuropsychological development. Findings suggest HC growth during uterine life among healthy infants may not be an important marker of early-life neurodevelopment but may be marginally useful with specific populations.

Ehm O.,Institute of Developmental Genetics | Goritz C.,Karolinska Institutet | Covic M.,Institute of Developmental Genetics | Schaffner I.,Institute of Developmental Genetics | And 11 more authors.
Journal of Neuroscience | Year: 2010

The generation of new neurons from neural stem cells in the adult hippocampal dentate gyrus contributes to learning and mood regulation. To sustain hippocampal neurogenesis throughout life, maintenance of the neural stem cell pool has to be tightly controlled. We found that the Notch/RBPJκ- signaling pathway is highly active in neural stem cells of the adult mouse hippocampus. Conditional inactivation of RBPJκ in neural stem cells in vivo resulted in increased neuronal differentiation of neural stem cells in the adult hippocampus at an early time point and depletion of the Sox2-positive neural stem cell pool and suppression of hippocampal neurogenesis at a later time point. Moreover, RBPJκ-deficient neural stem cells displayed impaired self-renewal in vitro and loss of expression of the transcription factor Sox2. Interestingly, we found that Notch signaling increases Sox2 promoter activity and Sox2 expression in adult neural stem cells. In addition, activated Notch and RBPJκ were highly enriched on the Sox2 promoter in adult hippocampal neural stem cells, thus identifying Sox2 as a direct target of Notch/RBPJκ signaling. Finally, we found that overexpression of Sox2 can rescue the self-renewal defect in RBPJκ-deficient neural stem cells. These results identify RBPJκ-dependent pathways as essential regulators of adult neural stem cell maintenance and suggest that the actions of RBPJκ are, at least in part, mediated by control of Sox2 expression. Copyright © 2010 the authors.

PubMed | University Pompeu Fabra, Genetic and Molecular Epidemiology Group, University of Vic, Hospital Universitario Of Elche and 4 more.
Type: Comparative Study | Journal: PloS one | Year: 2014

The relationship between inflammation and cancer is well established in several tumor types, including bladder cancer. We performed an association study between 886 inflammatory-gene variants and bladder cancer risk in 1,047 cases and 988 controls from the Spanish Bladder Cancer (SBC)/EPICURO Study. A preliminary exploration with the widely used univariate logistic regression approach did not identify any significant SNP after correcting for multiple testing. We further applied two more comprehensive methods to capture the complexity of bladder cancer genetic susceptibility: Bayesian Threshold LASSO (BTL), a regularized regression method, and AUC-Random Forest, a machine-learning algorithm. Both approaches explore the joint effect of markers. BTL analysis identified a signature of 37 SNPs in 34 genes showing an association with bladder cancer. AUC-RF detected an optimal predictive subset of 56 SNPs. 13 SNPs were identified by both methods in the total population. Using resources from the Texas Bladder Cancer study we were able to replicate 30% of the SNPs assessed. The associations between inflammatory SNPs and bladder cancer were reexamined among non-smokers to eliminate the effect of tobacco, one of the strongest and most prevalent environmental risk factor for this tumor. A 9 SNP-signature was detected by BTL. Here we report, for the first time, a set of SNP in inflammatory genes jointly associated with bladder cancer risk. These results highlight the importance of the complex structure of genetic susceptibility associated with cancer risk.

Pinho A.V.,CSIC - National Center for Metallurgical Research | Pinho A.V.,Institute Municipal dInvestigacio Medica Hospital del Mar | Rooman I.,Institute Municipal dInvestigacio Medica Hospital del Mar | Rooman I.,Vrije Universiteit Brussel | And 7 more authors.
Gut | Year: 2011

Objective: Acinar cells display plasticity in vitro and in vivo and can activate a variety of differentiation programmes that may contribute to pancreatic diseases. The aims were to determine: (1) the differentiation potential of acinar cells under conditions which favour stem cell survival, and (2) its relationship to the phenotypes acquired by pancreatic epithelial cells in chronic pancreatitis. Design: Murine acinar cells were cultured in suspension and their molecular phenotype was characterised by qRT-PCR, chromatin immunoprecipitation, immunocytochemistry and global transcriptome analysis. These findings were compared to the changes occurring in experimental chronic pancreatitis induced by pancreatic duct ligation and chronic caerulein administration. Results: Acinar cells in suspension culture acquired a dedifferentiated phenotype characteristic of pancreatic embryonic progenitors, consisting of the co-expression of Ptf1a and Pdx1, presence of an embryonic-type PTF1 transcriptional complex, activation of the Notch pathway, and expression of additional pancreatic progenitor cell markers such as CpA1, Sox9 and Hnf1b. A senescence programme, associated with activation of Ras and ERK signalling, limited the proliferative capacity of the cells. A similar progenitor-like phenotype with activation of a senescence programme was observed in experimental chronic pancreatitis induced by pancreatic duct ligation or repeated caerulein administration, with the concomitant and differential activation of proliferation and senescence in distinct cell populations. Conclusions: Acinar cells dedifferentiate into an embryonic progenitor-like phenotype upon suspension culture. This is associated with the activation of a senescence programme. Both processes take place in experimental chronic pancreatitis where senescence may contribute to limit tumour progression.

Pascual M.,Hospital Del Mar | Pascual M.,Institute Municipal dInvestigacio Medica Hospital Del Mar | Alonso S.,Hospital Del Mar | Alonso S.,Institute Municipal dInvestigacio Medica Hospital Del Mar | And 6 more authors.
British Journal of Surgery | Year: 2011

Background: Several studies have suggested that laparoscopy might confer an oncological advantage in patients undergoing surgery for colonic cancer. A decreased inflammatory and angiogenic response has been proposed. This study compared the local and systemic inflammatory and angiogenic responses after open and laparoscopic surgery for colonic cancer. Methods: Some 122 patients with colonic cancer were randomized to open or laparoscopic colectomy. Levels of interleukin (IL) 6 and vascular endothelial growth factor (VEGF) were measured in serum and peritoneal fluid at baseline, then at 4, 12, 24 and 48 h and on day 4 after surgery. Samples obtained on day 4 were tested in an in vitro angiogenesis assay, with measurement of number of capillaries per field and capillary length. Results: The serum IL-6 level was lower in the laparoscopic group at 4 h (mean(s.d.) 124(110) versus 244(326) pg/dl after open colectomy; P = 0·027). The serum VEGF concentration was also lower in the laparoscopic group at 48 h and day 4 (430(435) versus 650(686) pg/dl; P = 0·001). Overall, local IL-6 and VEGF levels were significantly higher than serum levels but there were no differences between groups. In vitro, postoperative serum and peritoneal fluid samples were potently angiogenic but there were no differences between open surgery and laparoscopy. Rates of tumour recurrence and survival were similar in the two groups. Conclusion: Despite differences in postoperative serum levels of IL-6 and VEGF after open and laparoscopic surgery in patients with colonic cancer, the angiogenic response is comparable in both surgical approaches. Copyright © 2010 British Journal of Surgery Society Ltd.

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